The prolongation of life

white, born in France, and more than 99 (mean 103.1) years old on the day we collected blood. We selected 492 controls from unrelated white people who were born in France and matched the centenarians for sex and geographic origin (mean age 51.2 years). The treating doctor completed a detailed health questionnaire and the results of the last blood test were collected for each person. We amplified the HFE gene using a polymerase chain reaction, and we detected the C282Y mutation using denaturing high performance liquid chromatography on a Wave DNA Fragment Analysis System (Transgenomic, Crewe). The centenarians included 44 heterozygotes and the matched controls contained 42 heterozygotes; the difference is not statistically significant even taking sex into account (table). The odds ratio of becoming centenarian when carrying the C282Y mutation was 1.08 (95% confidence interval 0.70 to 1.66), encompassing the value of 1 expected under the null hypothesis. We found two homozygotes for the C282Y mutation among the centenarians and one among the controls; all were women. None had been treated by phlebotomy and none had been diagnosed with haemochromatosis. Distributions of the genotypes in the control and in the centenarian groups satisfied Hardy-Weinberg equilibrium, which is not in favour of a selection against either homozygotes or heterozygotes for the C282Y mutation among centenarians.

phisme Humain). 3 The 80 men and 412 women were white, born in France, and more than 99 (mean 103.1) years old on the day we collected blood. We selected 492 controls from unrelated white people who were born in France and matched the centenarians for sex and geographic origin (mean age 51.2 years). The treating doctor completed a detailed health questionnaire and the results of the last blood test were collected for each person. We amplified the HFE gene using a polymerase chain reaction, and we detected the C282Y mutation using denaturing high performance liquid chromatography on a Wave DNA Fragment Analysis System (Transgenomic, Crewe). 4 The centenarians included 44 heterozygotes and the matched controls contained 42 heterozygotes; the difference is not statistically significant even taking sex into account (table). The odds ratio of becoming centenarian when carrying the C282Y mutation was 1.08 (95% confidence interval 0.70 to 1.66), encompassing the value of 1 expected under the null hypothesis.
We found two homozygotes for the C282Y mutation among the centenarians and one among the controls; all were women. None had been treated by phlebotomy and none had been diagnosed with haemochromatosis. Distributions of the genotypes in the control and in the centenarian groups satisfied Hardy-Weinberg equilibrium, which is not in favour of a selection against either homozygotes or heterozygotes for the C282Y mutation among centenarians.

Comment
Complications thought to be associated with heterozygosity for the C282Y mutation of the HFE gene, such as carcinomas or cardiovascular diseases, did not deplete a centenarian population of heterozygotes for C282Y. Heterozygosity for C282Y does not seem to be a risk factor for these common life threatening conditions. Finding people over 99 years old who are homozygous for the C282Y mutation and still alive without treatment confirms that clinical penetrance in homozygotes for the C282Y mutation is incomplete, as recently suggested in a study of more than 41 000 people in California. 5 That longevity is not compromised by either being a heterozygous or homozygous carrier of the C282Y mutation precludes the recommendation of population genetic testing for C282Y. Rather, alternative strategies should be implemented to improve early detection of hereditary haemochromatosis in people with abnormal indexes of iron metabolism and their close relatives.
Contributors: HC and MPR conceived and designed the study, analysed the data, and wrote the manuscript. MB, SF, and NB helped with genotypings and analyses. HB is in charge of the Chronos Project at the Foundation Jean Dausset-CEPH and provided the centenarian and control DNAs used for this study. All authors approved the final version of the manuscript. MPR is guarantor.
Competing interests: None declared.
Ethical approval: Ethics committee (CCPPRB) of the Hospital Saint-Antoine, Paris.

(Accepted 29 April 2003)
Genotypes at the C282Y mutation site in centenarians and controls* *The lower frequency of C282Y carriers in men (3.8% in centenarians v 2.5% in controls) compared with females (10.4% v 9.9%) reflects the uneven distribution of the geographic origin in men and women; of the centenarians, 26% of women and only 10% of men were born in the northwest of France, where the C282Y allele is much more common than in any other region. This underlines the necessity of a careful matching in case control studies to avoid the risk of finding spurious associations solely due to population stratification. †According to Hardy-Weinberg equilibrium; expected and observed numbers do not differ significantly.

One hundred years ago
The prolongation of life Tobacco and snuff